N-(3-phenyl-2h-tetrazole)-alkanoyl amines

ABSTRACT

A series of amide derivatives of omega-5-aryl-2-tetrazolylalkanoic acids derived from cyclic amines. These compounds are useful as anti-inflammatory agents.

United States Patent Buckler [4 1 Aug. 1, 1972 [54]N-(3-PHENYL-2H-TETRAZOLE)- 3,450,750 6/1969 Cragoe ..260/521 ALKANOYLAMINES 3,452,079 6/1969 Shen et al. ..260/469 3,453,312 7/1969 Spragueet a1. ..260/455 [72] Invent a?" 3,517,051 6/1970 Bolhofer ..260/4733,453,285 7/1969 Hayao ..260/308 [73] Assignee: Miles Laboratories,Inc., Elkhart,

Primary Examiner-Alex Mazel [22] Filed; Dec. 24, 1969 AssistantExaminer-Jose Tovar Attorney-Joseph C. Schwalbach, Michael A. Kond- [21]Appl' 888068 zella, Louis E. Davidson and Harry T. Stephenson [52] US.C1...260/247.5 R, 260/308 D, 260/ig4./72l3 [57] ABSTRACT [51] Int. Cl...C07d 87/40 A series of amide derivatives of omega-5-ary1-2- [58] Fieldof Search ..260/247.5 R, 308 D, 294.7 E tetrazolyI-alkanoic acidsderived from cyclic amines. These compounds are useful asanti-inflammatory [56] References Cited agents.

UNITED STATES PATENTS 8 Claims, No Drawings 3,083,204 3/1963 Klavehn eta1. ..260/292 N-(3-PHENYL2H-TETRAZOLD-ALKANOYL AMINES SUMMARY OF THEINVENTION The compounds of this invention may be represented by the N-NCH2n-tiiR structural formula Ar-C in which Ar is halogen substitutedphenyl, n is l to 4, and R is a monocyclic heterocyclicnitrogen-containing radical in which the attachment to the carbonylgroup is through the nitrogen atom. For example R may be piperidyl,pyrrolidyl, or morpholino.

The novel compounds of this invention can be readily prepared byamination of a tetrazolyl acyl halide using the appropriatelysubstituted tetrazolyl alkanoic acid as a precursor for the acyl halide,which is readily formed by halogenation thereof. Suitable halogenatingagents include cyanuric chloride, phosphorus pentachloride, thionylchloride and the like. The tetrazolyl acyl halide is then aminated usingthe appropriate cyclic amine. Although the conditions of the reactionsare not critical, it is preferred to conduct the halogenation in asuitable solvent such as chloroform. The amination reaction is alsosuitably conducted in a solvent for the amine. Suitable solvents includetetrahydrofuran and the like. The halogenation reaction may beadvantageously conducted under reflux while the amination reaction issatisfactorily run at room temperature. Other solvents for thehalogenation reaction are benzene and toluene and other halogenatingagents are thionyl bromide and phosphorus oxychloride.

The omega-5-aryl-2-tetrazolyl alkanoic acid starting materials may beprepared in accordance with the procedure described in US. Pat. No.3,453,285to Shin I-Iayao.

Preparation of these compounds may be illustrated in the followingseries of equations in which the various radicals are as indicatedabove.

The compounds of this invention are useful as antiinflammatory agents.

Suitable medications may be prepared by combining one or more of thecompounds of this invention as an active ingredient with fillers,carriers, extenders and excipients generally used in pharmaceuticalformulations. Medications may be prepared in solid or liquid states astablets, capsules, suspensions and similar dosage forms suitable fororal, intraperitoneal and other convenient means of administration. Theactive ingredients may be mixed with common diluents or tabletingadjuncts such as cellulose powder, com-starch, lactose, talc and thelike according to accepted manufacturing practices. Unit dosages (inmg.) of active ingredients in the medication may be varied so that theamount used is adequate to provide the desired therapeutic resultwithout untoward side effects and to permit satisfactory variation indosages administered.

Anti-inflammatory activity was observed when medications includingcompounds of this invention as an active ingredient were administeredorally to randomly selected groups of rats weighing between 260 and 400grams. The active ingredients were evaluated according to a procedure inwhich pleurisy was induced by interpleural administration of Evans Blueand Carrageenen (0.075 percent Evans Blue-0.025 percent Carrageenen).The anti-inflammatory medication was given orally 1 hour before theinterpleural administration of the solution. At 6 hours the animals weresacrificed and the pleural exudate was measured.

Groups of seven animals were used for each evalua tion. In this assayphenylbutazone produced a percent decrease in pleural exudate of 31.1percent. By way of comparison the compound of Example I produced apercent decrease of 61.2 percent. The relative potency of this compoundat percent confidence levels determined at half log dose intervalscompared to phenylbutazone was therefore 4.98 to l [3.61-5.36]. Othercompounds of this invention gave similar results.

DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLE 1N-3-[5'-(3"-(3-Bromophenyl)-2'I-I- tetrazole]propionyl piperidine Amixture of 32 g. (0.108 mole) of 3-[5-(3"- bromophenyl)-2'H-tetrazole]propionic acid and 80 g. of thionyl chloride in 250 ml.of dry chloroform was stirred under reflux for 16 hours. Evaporation ofthe solvent and excess reagent under reduced pressure gave a tan oilwhich was redissolved in 300 ml. of dry tetrahydrofuran. To this wasadded 20 ml. of redistilled piperidine in ml. of dry tetrahydrofuran.The mixture was stirred for 15 minutes at room temperature. Thetetrahydrofuran was then removed under reduced pressure and the residuewell triturated with one liter of 0.1 N hydrochloric acid. The resultingsemi-solid was taken up in 700 ml. of ether and extracted with 300 ml.of 3 percent aqueous sodium bicarbonate solution. The ether solution wasthen dried over calcium chloride, filtered, and cooled in therefrigerator. This deposited 25 g. (69 percent) of tan needles, mp. 69C., of N-3-[5'- (3" -bromophenyl) -2'H-tetrazole]propionylpiperidine.

Calculated for c,,H,,N,oBr; C, 49.46; H, 4.98.

Found: C, 49.66; H, 5.49.

The infrared spectrum (10 percent, CHCl displayed the expected tertiaryamide absorption at 1,640 cm".

EXAMPLE 2 N-3-[ 5 3 '-Fluorophenyl)-2'H-tetrazole] propionylpiperidineUsing the procedure of Example 1, there was obtained from 7 g. (0.029mole) of 3-[5-(3"-fluorophenyl)-2'H tetrazole1propionic acid, 8 g. (91percent) of N-3-[ 5 3 -fluorophenyl)-2H-tetrazolelpropionylpiperidine,mp 95 C., after recrystallization from aqueous ethanol.

Calculated for C H FN O; C, 59.40; H, 5.94.

Found: C, 59.33; H, 6.07.

EXAMPLE 3 N-3-[ S 3 ,5 '-Dibromophenyl )-2'H-tetrazole]propionylpiperidine Using the procedure of Example 1, therewas obtained from 10 g. (0.027 mole) of 3-[5'-(3",5"-dibromophenyl)-2'H-tetrazole]propionic acid, 9.5 g. (81 percent) ofN-3-[5-(3",5"-dibromophenyl) -2'H- tetrazole]propionylpiperidine, mp.115 C., after recrystallization from aqueous methanol.

Calculated for C H B1 N O2 C, 40.61; H, 3.86.

Found: C, 40,86; H, 3.78.

EXAMPLE 4 N-3-[ 5 3 '-Chlorophenyl)-2H-tetrazole ]propionylpiperidineUsing the procedure of Example 1, there was obtained from 5 g. (0.02mole) of 3-[5'-(3"-chlorophenyl)-2'H-tetrazole]propionic acid, 3.3 g.(52 percent) of N-3-[ 5 @6 3 -chlorophenyl)-2'H-tetrazole1-propionylpiperidine, mp. 70 C., after recrystallizationfrom heptane.

Calculated for c n cm o; C, 56.33; H, 5.64. Found: C, 56.79; H, 5.82.

EXAMPLE 5 N-3-[ 5 3 ,5 '-Dichlorophenyl)-2 'H-tetrazole]propionylpyrrolidine EXAMPLE 6 N-3-[5-3"-Bromophenyl)-2'H-tetrazolelpropionylmorpholine Using the procedure of Example 1 andmorpholine instead of piperidine there was obtained from 7 g. (0.024mole) of 3-[5'-(3"-bromophenyl)-2'-H- tetrazolelpropionic acid, 6 g. (68percent) of N-3-[5'- 3 -bromophenyl)-2H-tetrazole1propionylmorpho line,mp. 129 C., after recrystallization from aqueous methanol.

Calculated for C14H6B1'N502 C, 45.91; H, 4.40.

Found: C, 45.90; H, 4.57.

EXAMPLE 7 N-3-[5-(3"-BromophenyD-Z'H- tetrazole]propionylpyrrolidineUsing the procedure of Example 1 and pyrrolidine instead of piperidinethere was obtained from 17 g. (0.057 mole) of 3-[5-(3"bromophenyl)-2 H-tetrazolelpropionic acid, 7.1 g. (36 percent) of N-3-[5 3 '-bromophenyl)-2' H-tetrazole lpropionylpyrrol idine, mp. C., after recrystallizationfrom heptane.

Calculated for c H BrN Oz C, 48.01: H, 4.62.

Found: C, 48.25; H, 5.00.

What is claimed is:

l. A compound selected from the group consisting of compounds of theformula:

in which Ar is halophenyl, n is l to 4 and R is piperidino, pyrrolidinoor morpholine.

2. A compound according to claim 1 which is N-3-[5 3'-bromophenyl)-2H-tetrazole lpropionylpiperidine.

3. A compound according to claim 1 which is N-3-[ 5 3'-fluorophenyl)-2'H-tetrazole lpropionylpiperidine.

4. A compound according to claim 1 which is N-3-[5 3 ,5'-dibromophenyl)-2'H-tetrazole]propionylpiperidine.

5. A compound according to claim 1 which is N-3-{5 3 -chlorophenyl)-2'H-tetrazole1propionylpiperidine.

6. A compound according to claim 1 which is N-3-[5 3 ,5'-dichlorophenyl)-2 H tetrazole]propionylpyrrolidine.

7. A compound according to claim 1 which is N-3-[5 3' -bromophenyl )-2'H-tetrazole ]propionylmorpholine.

8. A compound according to claim I which is N-3-[5 3 '-bromophenyl)-2Htetrazole]propionylpyrrolidine.

2. A compound according to claim 1 which isN-3-(5''-(3''''-bromophenyl)-2''H-tetrazole)propionylpiperidine.
 3. Acompound according to claim 1 which isN-3-(5''-(3''''-fluorophenyl)-2''H-tetrazole)propionylpiperidine.
 4. Acompound according to claim 1 which isN-3-(5''-(3'''',5''''-dibromophenyl)-2''H-tetrazole)propionylpiperidine.5. A compound according to claim 1 which isN-3-(5''-(3''''-chlorophenyl)-2''H-tetrazole) propionylpiperidine.
 6. Acompound according to claim 1 which isN-3-(5''-(3'''',5''''-dichlorophenyl)-2''H tetrazole)propionylpyrrolidine.
 7. A compound according to claim 1 which isN-3-(5''-(3''''-bromophenyl)-2''H-tetrazole)propionylmorpholine.
 8. Acompound according to claim 1 which isN-3-(5''-(3''''-bromophenyl)-2''H-tetrazole)propionylpyrrolidine.